Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy

Sandoval, Ruben M.; Kennedy, Michael D.; Low, Philip S.; Molitoris, Bruce A.

doi:10.1152/ajpcell.00006.2004

Cited by 135 publications

(125 citation statements)

References 51 publications

(43 reference statements)

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“…Folate conjugates were synthesized as reported in the literature (37,38). Anti-FR polyclonal antibodies, PU9, PU10, and PU17, were purified by affinity column chromatography and transferred to PBS (pH 9.0) for conjugation.…”

Section: Methodsmentioning

confidence: 99%

In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry

He¹,

Wang

Hartmann

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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270

276

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Quantitation of circulating tumor cells (CTCs) constitutes an emerging tool for the diagnosis and staging of cancer, assessment of response to therapy, and evaluation of residual disease after surgery. Unfortunately, no existing technology has the sensitivity to measure the low numbers of tumor cells (<1 CTC per ml of whole blood) that characterize minimal levels of disease. We present a method, intravital flow cytometry, that noninvasively counts rare CTCs in vivo as they flow through the peripheral vasculature. The method involves i.v. injection of a tumor-specific fluorescent ligand followed by multiphoton fluorescence imaging of superficial blood vessels to quantitate the flowing CTCs. Studies in mice with metastatic tumors demonstrate that CTCs can be quantitated weeks before metastatic disease is detected by other means. Analysis of whole blood samples from cancer patients further establishes that human CTCs can be selectively labeled and quantitated when present at Ϸ2 CTCs per ml, opening opportunities for earlier assessment of metastatic disease.folate conjugates ͉ in vivo imaging ͉ multiphoton microscopy ͉ metastasis ͉ cancer diagnosis

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Section: Methodsmentioning

confidence: 99%

In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry

He¹,

Wang

Hartmann

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

270

276

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“…Substantial expression of the folate receptor in the proximal tubule cells of the kidneys results in commonly high and specific renal uptake of folate-based radioconjugates (9,10). As a consequence there is an inherent risk of damage to the kidneys by particle radiation.…”

Section: Introductionmentioning

confidence: 99%

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

Reber

Haller

Leamon

et al. 2013

Molecular Cancer Therapeutics

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Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folatebased radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate 177 Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of 177 Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with 177 Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of 177 Lu-EC0800 with PMX ther resulted in a two-to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMX subther or untreated control mice. PMX subther protected the kidneys from undesired side effects of 177 Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using 99m Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity. Mol Cancer Ther; 12(11); 2436-45. Ó2013 AACR.

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“…27 Folate is absorbed by the kidney, predominantly in the proximal tubule, which fortuitously is a site particularly at risk during ischemia. 28 The binding of folate to the folate receptor occurs at a relatively high affinity with half maximal binding as high as 12 nM in human proximal tubule cells, making it ideal for pharmacological targeting. 25,26,29 In this study, we synthesized a novel folate-antioxidant conjugate to selectively target the kidney, to enhance localized superoxide scavenging, and to prevent the development of ARF while avoiding the associated side effects of systemic antioxidant therapy.…”

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confidence: 99%

Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury

Knight

Kundu

Joseph

et al. 2012

Journal of the American Society of Nephrology

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Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here, we developed a directed therapeutic that specifically targets an antioxidant to renal proximal tubule cells via the folate receptor. Because a local increase in superoxide contributes to renal ischemic injury, we created the folate-antioxidant conjugate 4-hydroxy-Tempo (tempol)-folate to target folate receptors, which are highly expressed in the proximal tubule. Dihydroethidium high-performance liquid chromatography demonstrated that conjugated tempol retained its efficacy to scavenge superoxide in proximal tubule cells. In a mouse model of renal ischemia-reperfusion injury, tempol-folate reduced renal superoxide levels more effectively than tempol alone. Furthermore, electron spin resonance revealed the successful targeting of the tempol-folate conjugate to the kidney and other tissues expressing folate receptors. Administration of tempol-folate protected the renal function of mice after ischemia-reperfusion injury and inhibited infiltration of macrophages. In conclusion, kidney-specific targeting of an antioxidant has therapeutic potential to prevent renal ischemic injury. Conjugation of other pharmaceuticals to folate may also facilitate the development of treatments for other kidney diseases.

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Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy

Abstract: . Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy.

Cited by 135 publications

References 51 publications

In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry

In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury

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